This proposal describes a 5-year training program for the development of an academic career in Pediatric Rheumatology. The PI has completed formal residency and fellowship training in Pediatrics and Pediatric Rheumatology at The Children's Hospital of Philadelphia and is currently expanding his scientific skills in immune tolerance and autoimmunity models. Dr. Gary Koretzky, an international authority in lymphocyte biology, will mentor the PI's scientific development. Dr. Koretzky is Vice Chair for Research, Chief Scientific Officer, and Francis C. Wood Professor of Medicine at the University of Pennsylvania. He has extensive experience in successfully mentoring students, post-doctoral fellows, and junior faculty members. To further promote the investigator's scientific development, an Advisory Committee comprising highly regarded medical scientists including Drs. Steven Reiner, Terri Finkel, and Edward Behrens has been established. Sjgren syndrome experts Drs. Seunghee Cha and Eduardo M. Rocha will participate in advisory roles as well. Drs. Finkel and Behrens are also leaders in Pediatric Rheumatology and will mentor the PI's clinical development. The proposed research focuses on mechanisms of immune dysregulation in the development of Sjgren syndrome, a common but poorly understood autoimmune disease. Sjgren syndrome is caused by destruction and dysfunction of lacrimal and salivary glands with subsequent profound ocular and oral dryness which may progress to sight-threatening or severe dental manifestations. The nonobese diabetic (NOD) mouse spontaneously develops autoimmunity resembling Sjgren syndrome, providing a tool for studying disease initiation. Inflammatory cell infiltrates of lacrimal and salivary glands are dominated by T cells, but the contributions of different T cell subsets in disease initiation are unknown. Regulatory T cells, a subset of CD4+ T cells which prevent autoimmunity in normal hosts, are organized anatomically in non-autoimmune-prone mice; however, whether this is disrupted in autoimmune-prone mice is unknown. Female NOD mice develop salivary gland inflammation, whereas males develop lacrimal gland disease. Whether this is due to immune- cell intrinsic or extrinsic mechanisms is unknown. This proposal specifically aims to: 1) define the roles of CD8+ and CD4+ T cells in disease initiation; 2) define the extent and mechanisms of regulatory T cell defects in the NOD model of Sjgren syndrome. Understanding the earliest events in the development of Sjgren syndrome autoimmunity will provide targets for better diagnostic and therapeutic modalities for use in this and other autoimmune diseases. PUBLIC HEALTH RELEVANCE: Sjgren syndrome is an autoimmune disease characterized by destruction of tear and saliva producing glands resulting in profound dry eye and dry mouth which may result in sight-threatening or severe dental complications. Despite being one of the most common autoimmune rheumatologic diseases, affecting up to 4 million Americans, the cause of Sjgren syndrome is unknown. This proposal is aimed at identifying the components of the immune system which are responsible for the initiation of inflammation of lacrimal and salivary glands, which will provide targets for better diagnostic and therapeutic modalities for use in this and other autoimmune diseases.